Photochemical Synthesis of 2-Azabicyclo[3.2.0]heptanes: Advanced

ACS2GO © 2019. ← → → ←. loading. To add this web app to the home screen open the browser option menu and tap on Add to homescreen...
0 downloads 0 Views 2MB Size
Download PDF
Article Cite This: J. Org. Chem. 2018, 83, 1394−1401

pubs.acs.org/joc

Photochemical Synthesis of 2‑Azabicyclo[3.2.0]heptanes: Advanced Building Blocks for Drug Discovery. Synthesis of 2,3-Ethanoproline Tetiana Druzhenko,†,‡ Yevhen Skalenko,†,‡ Maryna Samoilenko,‡ Aleksandr Denisenko,‡ Sergey Zozulya,‡ Petro O. Borysko,‡ Maria I. Sokolenko,‡ Alexandr Tarasov,‡ and Pavel K. Mykhailiuk*,‡,§ ‡

Enamine Ltd., Chervonotkatska 78, Kyiv 02094, Ukraine, www.enamine.net Institute of High Technologies, Taras Shevchenko National University of Kyiv, Glushkov Avenue 4g, Kyiv 03022, Ukraine § Department of Chemistry, National Taras Shevchenko University of Kyiv, Volodymyrska 64, Kyiv 01033, Ukraine †

S Supporting Information *

ABSTRACT: Intramolecular photochemical [2 + 2]-cyclization of acetophenone enamides gave 2-azabicyclo[3.2.0]heptanes, advanced building blocks for drug discovery. Synthesis of a conformationally restricted analogue of proline, 2,3-ethanoproline, was performed.

■

INTRODUCTION

Conformationally restricted compounds are popular in modern medicinal chemistry.1 Fixation of functional groups in a biologically active conformation often leads to an enhanced biological activity, selectivity and metabolic stability.2 In this context, in recent years medicinal chemists have often used 3D-shaped building blocks with high fractions of (F)sp3-hybridized carbon atoms.3,4 Bicyclic amines A−D can be considered as conformationally restricted surrogates for pyrrolidine, piperidine, and azepane that altogether are present in more than 100 FDA-approved drugs (Table 1, Figure 1). Surprisingly, although motifs A−C play an important role in drug discovery projects,5,6 compounds D remain largely unexplored. We presume that the key reason is the lack of synthetic approaches. Motifs D only with multiple

Figure 1. Mono- and bicyclic cores in drug discovery.

substitution at the 2-azabicyclo[3.2.0]heptane skeleton are described in the literature.7 Therefore, herein we report a practical synthesis and physicochemical properties of building blocks D with two exit vectors and no additional substitution (Figure 1).

■

RESULTS AND DISCUSSION [2 + 2]-Photocycloaddition has been used for the synthesis of cyclobutanes for more than 100 years.8 In 1999, Piotrowski described the [2 + 2]-photocyclization of substrates 1 into the substituted pyrrolidines 2.9 Also, this methodology was used in the synthesis of 2,4-methanoprolines (2, R = CO2Et).10 We decided to take advantage of this approach by replacing the fragment of allylamine with homoallylamine (Scheme 1).11 1. Starting Compounds. First, we prepared Schiff base 5 from acetophenone and homoallylamine. When the subsequent reaction of 5 with (CF3CO)2O was performed in pyridine, unexpected product 6 was isolated in 38% yield. Performing the reaction in THF with NEt3, however, gave the needed enamide 7 in 93% yield (Scheme 2). 2. Optimization. Next, we tried the [2 + 2]-photocyclization of compound 7 under different conditions (Table 2). In acetonitrile at 254 nm at room temperature, formation of a complex mixture was observed. At 310 nm, after 24 h at room

Table 1. Bicyclic Pyrrolidines A−D in Drug Discovery

a

Substructure search in ChEMBL db. Reaxys db.5

b

Substructure search in

© 2018 American Chemical Society

Received: November 16, 2017 Published: January 3, 2018 1394

DOI: 10.1021/acs.joc.7b02910 J. Org. Chem. 2018, 83, 1394−1401

Article

The Journal of Organic Chemistry

concentrations, however, formation of unidentified side products was observed (Table 2, entry 9). 3. Scale. Finally, we studied this photochemical reaction at different scales. The synthesis on the milligram scale was performed at 5 mM in 5 mL glass vials. The reaction on a 25 g scale was efficiently performed at 100 mM in a common 1 L glass flask (Scheme 3).

Scheme 1. Previous Work (a) and This Work (b)

Scheme 3. Scaled-Up Synthesis of Compound 7a

Scheme 2. Synthesis of Starting Compound 7

4. Scope. Having a practical procedure in hand, we next studied its scope (Scheme 4). Aromatic (7, 8) and six (9, 10)- and Scheme 4. Scope of the Reaction

Table 2. Optimization of the Synthesis of Compound 7a

entry

λ (nm)

c (mM)

1 2 3 4 5 6 7 8 9

254 310 365 419 365 365 365 365 365

5 5 5 5 5 25 50 100 200

sensitizer − − − Ph2CO Ph2CO Ph2CO Ph2CO Ph2CO

(1.0 (1.0 (1.0 (1.0 (1.0

equiv) equiv) equiv) equiv) equiv)

conversion (%)a complex mixture 11 (7a+6)b 0 0 100 100 100 100 100c(side products)

a

Conversion of the reaction according to 19F NMR. bSlow formation of two compounds 7a and 6 (1/1) was observed. c100% conversion, 90% purity by 19F NMR.

temperature, the conversion of the reaction reached only 11%. Moreover, two products 7a and 6 (1/1) slowly formed. After 48 h of irradiation at 365 or 419 nm, the reaction had not proceeded at all. However, performing the reaction at 365 nm in the presence of benzophenone as a triplet sensitizer smoothly gave the “head-to-head” product 7a (Table 2, entry 5). In strict contrast to pyrrolidines 2, formation of analogous “headto-tail” piperidines was not observed (Scheme 1).12 All experiments above were performed under high dilution of 5 mM to avoid intermolecular cyclizations. For large scale synthesis, we determined that the reaction could be performed in up to 100 mM concentration (Table 2, entry 8). At higher

a

After 2 weeks of irradiation. bComplex mixture.

five (11−13)-membered heteroaromatic substrates smoothly gave the needed products 7a−13a in 65−93% yield. Aromatic compounds 14 and 15 with C−Br and C−I bonds did not react, however, even after 2 weeks of irradiation presumably due to the heavy atom effect. On the other hand, substrate 17 after 24 h of irradiation afforded an unidentified complex mixture. 1395

DOI: 10.1021/acs.joc.7b02910 J. Org. Chem. 2018, 83, 1394−1401

Article

The Journal of Organic Chemistry

Scheme 7. Synthesis of Monoprotected N-Boc Diamine 17

Nevertheless, product 14a was obtained in 34% yield after 2 weeks of irradiation under photoredox-catalysis: 419 nm, cat. Ir(ppy)3 (Scheme 5).13,14 We failed, however, to acheive [2 + 2]-photocyclization of substrate 15. Scheme 5. Photoredox-Catalyzed Synthesis of Compound 14a

Scheme 8. Synthesis of Amino Acid 18, a Conformationally Restricted Analogue of L-Proline

5. Synthesis of Building Blocks. We also wanted to show that the obtained compounds herein could easily be transformed into the appropriate building blocks for direct use in drug discovery projects. a. Amines. The alkaline cleavage of the CF3CO−N group in 7a−13a easily gave the needed amines 7b−13b as hydrochlorides in 89−98% yield. Compound 7b was obtained on a 10 g scale in one synthesis run. Structures of products 7b and 12b were confirmed by X-ray analysis (Scheme 6).15 6. Physicochemical Properties (ADME). Next, we measured the physicochemical characteristics of 2-azabicyclo[3.2.0]heptanes (core D) and compared them to the established scaffolds of pyrrolidine, piperidine, and azepane. All four compounds 20−23 demonstrated very close lipophilicity and water solubility. However, compound 23 was also less metabolically stable compared with 20−22. These data show that monosubstituted 2-azabicyclo[3.2.0]heptanes indeed have a potential to be considered as conformationally restricted surrogates for pyrrolidines, piperidines, and azapanes needed in modern medicinal chemistry projects (Table 3).

Scheme 6. Synthesis of Amines 7b−13b

Table 3. Experimental Physicochemical Parameters (ADME) of Model Compounds 20−23

b. Diamine. The standard N-Boc protection of amine 9b, followed by a hydrogenation of the pyridine ring, gave the mono N-Boc-protected diamine 17 as a mixture of two diastereomers. The reaction was performed in methanol at 50 °C over Pd/C as a catalyst (Scheme 7). c. Amino Acid. Finally, synthesis of amino acid 18,16 a conformationally rigid analogue of L-proline, was undertaken. An attempted oxidative cleavage of the phenyl ring in compound 8a with NaIO4/RuCl3 (cat.) unexpectedly gave the iodinated product 19 (X-ray, Scheme 8).15 Ozonolysis of 8a, followed by a cleavage of protecting groups, gave the target amino acid 18 in a low yield of 7%. Therefore, we next N-Bz-protected the furan derivative 11b and oxidized the furan ring with NaIO4/RuCl3 (cat). After hydrolysis of the N-Bz group, product 18 was isolated in 47% yield.

a

Experimental n-octanol/water distribution coefficient (log) at pH 10.0. Thermodynamic aqueous solubility (μM) in 50 mM phosphate buffer (pH 7.4). cIntrinsic clearance rate CLint (mg/(min·μL)) measured in mouse liver microsomes. b

7. Synthesis of Drug Analogues. To demonstrate the high potential of the synthesized bicyclic building blocks for drug discovery, we synthesized compound 24, a conformationally restricted fused analogue of bupivacaine, which is an FDAapproved local anesthetic (Scheme 9). Previously, we showed that spirocyclic analogue 25 was more active than bupivacaine.4c Unfortunately, compound 24 showed no anesthetic activity in vivo in mice using the tail flick test (Figure 2). To validate 1396

DOI: 10.1021/acs.joc.7b02910 J. Org. Chem. 2018, 83, 1394−1401

Article

The Journal of Organic Chemistry

standards. Mass spectra were recorded on an LC-MS instrument with chemical ionization (CI). LC-MS data were acquired on an Agilent 1200 HPLC system equipped with a DAD/ELSD/LCMS-6120 diodematrix and mass-selective detector, column: Poroshell 120 SBC18, 4.6 mm × 30 mm. Eluent, A, acetonitrile−water with 0.1% FA (99:1); B, water with 0.1% FA. ((1E)-N-(But-3-en-1-yl)-1-phenylethan-1-imine (5). Acetophenone (12.0 g, 100 mmol, 1.0 equiv), p-toluenesulfonic acid monohydrate (190 mg, 0.01 equiv., 1.0 mmol), and 10% solution of homoallylamine (10.6 g, 150 mmol, 1.5 equiv) in benzene were mixed in a 250 mL round-bottom flask and heated to reflux with a Dean− Stark apparatus. After 48 h of reflux (the reaction was monitored by NMR), the reaction mixture was evaporated under reduced pressure and the product (13.3 g, 77% yield) was immediately used in the next step without purification. (Z)-4-(But-3-en-1-ylamino)-1,1,1-trifluoro-4-phenylbut-3-en2-one (6). Imine 5 (1.7 g, 10 mmol, 1.0 equiv) was dissolved in pyridine (10 mL) and cooled to −10 °C under argon atmosphere, and trifluoroacetic anhydride (2.5 g, 12 mmol, 1.2 equiv) was added dropwise under inert atmosphere. The reaction mixture was warmed to room temperature, stirred for 30 min, and evaporated under reduced pressure. The residue was purified via column chromatography (hexanes/EtOAc = 10/1) to afford products 6 (1.0 g, 38% yield) and 7 (1.1 g, 42% yield) as yellow oils. 1H NMR (400 MHz, chloroform-d) δ 11.12 (s, 1H), 7.63−7.39 (m, 3H), 7.33 (dd, J = 7.5, 2.2 Hz, 2H), 5.69 (m, 1H), 5.38 (s, 1H), 5.27−4.88 (m, 2H), 3.33 (q, J = 6.7 Hz, 2H), 2.29 (q, J = 6.7 Hz, 2H). 13C NMR (126 MHz, chloroform-d) δ 176.2 (q, J = 32.9 Hz), 170.6, 134.0, 133.6, 130.5, 128.9, 127.5, 118.7, 117.8 (q, J = 288.5 Hz), 90.3, 44.8, 34.4. 19F NMR (376 MHz, chloroform-d) δ −77.05. LCMS (m/z): 270 (M + H+). Anal. Calcd for C14H14F3NO: C, 62.45; H, 5.24; N, 5.20. Found: C, 62.64; H, 5.05; N, 5.48. N-(But-3-en-1-yl)-2,2,2-trifluoro-N-(1-phenylvinyl)acetamide (7). Enamide 6 (26.9 g, 100 mmol, 1.0 equiv) was dissolved in triethylamine (150 mL) and cooled to −10 °C, and trifluoroacetic anhydride (25.2 g, 120 mmol, 1.2 equiv) was added dropwise under an inert atmosphere. The reaction mixture was warmed to room temperature, stirred for 30 min, and evaporated under reduced pressure. The residue was purified via column chromatography (hexanes/EtOAc = 10/1) to give the product (25.0 g, 93% yield) as a yellow oil. 1 H NMR (500 MHz, chloroform-d) δ 7.41 (s, 5H), 5.83 (s, 1H), 5.73 (m, 1H), 5.29 (s, 1H), 5.13−5.00 (m, 2H), 4.09 (broad s, 1H), 2.63 (broad s, 1H), 2.36 (s, 2H). 13C NMR (126 MHz, chloroform-d) δ 157.6 (q, J = 35.7 Hz), 143.5, 134.3, 134.2, 129.6, 129.0, 126.3, 117.4, 115.0, 116.7 (q, J = 288.4 Hz), 47.0, 31.4. 19F NMR (376 MHz, chloroform-d) δ −67.26. Anal. Calcd for C14H14F3NO: C, 62.45; H, 5.24; N, 5.20. Found: C, 62.13; H, 5.37; N, 5.03. N-(But-3-en-1-yl)-N-(1-(2,4-dimethoxyphenyl)vinyl)-2,2,2-trifluoroacetamide (8). Yellow oil. 2.7 g, 81% yield. Eluent for chromatography: hexanes/EtOAc = 4/1. 1H NMR (500 MHz, chloroformd) δ 7.13 (d, J = 8.4 Hz, 1H), 6.46 (m, 2H), 5.85−5.53 (m, 2H), 5.24 (s, 1H), 5.15−4.80 (m, 2H), 3.76 (m, 7H), 3.58−3.17 (broad s, 1H), 2.27 (m, 2H). 13C NMR (126 MHz, chloroform-d) δ 161.9, 159.1, 157.4 (q, J = 35.3 Hz), 140.4, 134.6, 130.5, 117.0, 116.8 (q, J = 288.0 Hz), 116.7, 115.5, 104.9, 99.1, 55.4, 55.3, 46.5, 31.2. 19F NMR (376 MHz, chloroform-d) δ −66.62. LCMS (m/z): 330 (M + H+). Anal. Calcd for C16H18F3NO3: C, 58.35; H, 5.51; N, 4.25. Found: C, 58.19; H, 5.35; N, 4.17. N-(But-3-en-1-yl)-2,2,2-trifluoro-N-(1-(pyridin-3-yl)vinyl)acetamide (9). Yellow oil. 20.6 g, 76% yield. Eluent for chromatography: hexanes/EtOAc = 2/1. 1H NMR (400 MHz, chloroform-d) δ 8.59 (d, J = 2.8 Hz, 1H), 8.47 (m, 1H), 7.57 (d, J = 8.0 Hz, 1H), 7.21 (m, 1H), 5.79 (s, 1H), 5.56 (m Hz, 1H), 5.27 (s, 1H), 5.02−4.75 (m, 2H), 4.22−2.57 (broad m, 2H), 2.23 (m, 2H). 13 C NMR (101 MHz, chloroform-d) δ 157.2 (q, J = 35.7 Hz), 150.4, 147.5, 140.7, 133.8, 133.2, 129.8, 123.5, 117.4, 116.9 (q, J = 2.4 Hz), 116.3 (q, J = 288.2 Hz), 46.6, 31.1. 19F NMR (376 MHz, chloroform-d) δ −67.34. LCMS (m/z): 271 (M + H+). Anal. Calcd for C13H13F3N2O: C, 57.78; H, 4.85; N, 10.37. Found: C, 57.45; H, 4.49; N, 10.71.

Scheme 9. Synthesis of Conformationally Restricted Analogues of Bupivacaine: Compounds 24 (a) and 25 (b, previous work)4c

Figure 2. Anesthetic activity of compound 24 and bupivacaine in mice in vivo (tail flick test).

the utility of 2-azabicyclo[3.2.0]heptanes in drug discovery, more biological targets are needed.

■

SUMMARY We developed a two-step synthesis of 2-azabicyclo[3.2.0]heptanes with two exit vectors. The syntheses commenced from the aromatic and heteroaromatic acetophenones. The photochemical [2 + 2]-cycloaddition step was performed on a 25 g scale. The model 2-azabicyclo[3.2.0]heptanes possessed similar lipophilicity and water solubility compared to the corresponding pyrrolidines and piperidines but had a lower metabolic stability. The corresponding analogue 24 of bupivacaine was inactive: it showed no anesthetic activity in vivo in mice using the tail flick test. Nevertheless, given the available starting materials, and the practical synthesis, we believe that medicinal chemists will soon start to use 2-azabicyclo[3.2.0]heptanes in drug discovery programs.

■

EXPERIMENTAL SECTION

All starting materials were obtained from Enamine, Ltd. Column chromatography was performed using Kieselgel Merck 60 (230−400 mesh) as the stationary phase. Reverse phase column chromatography was performed using C18-modified silica gel as a stationary phase, column: SunFire Waters, 5 μm, 19 mm × 100 mm. 1H, 19F, and 13C NMR spectra were recorded on a 500 or 400 MHz, 376 MHz, and 125 or 101 MHz instrument, respectively. Chemical shifts are reported in ppm downfield from TMS (1H, 13C) or CFCl3 (19F) as internal 1397

DOI: 10.1021/acs.joc.7b02910 J. Org. Chem. 2018, 83, 1394−1401

Article

The Journal of Organic Chemistry N-(But-3-en-1-yl)-2,2,2-trifluoro-N-(1-(pyrazin-2-yl)vinyl)acetamide (10). Yellow oil. 2.4 g, 89% yield. Eluent for chromatography: MTBE (was obtained in ca. 90% purity). 1H NMR (400 MHz, chloroform-d) δ 8.61 (d, J = 1.5 Hz, 1H), 8.54−8.25 (m, 2H), 6.39 (s, 1H), 5.83−5.40 (m, 2H), 4.98−4.83 (m, 2H), 4.43−3.75 (broad s, 1H), 3.24−2.58 (broad s, 1H), 2.31−2.12 (m, 2H). 13 C NMR (101 MHz, chloroform-d) δ 157.1 (q, J = 36.0 Hz), 147.7, 144.4, 144.1, 141.4, 140.6, 133.9, 120.7, 117.3, 116.2 (q, J = 288.3 Hz), 47.6, 31.2. 19F NMR (376 MHz, chloroform-d) δ −68.28. LCMS (m/z): 272 (M + H+). N-(But-3-en-1-yl)-2,2,2-trifluoro-N-(1-(furan-2-yl)vinyl)acetamide (11). Yellow oil. 29.1 g, 56% yield. Eluent for chromatography: hexanes/EtOAc = 10/1 (was obtained in ca. 90% purity). 1 H NMR (400 MHz, chloroform-d) δ 7.43 (s, 1H), 6.43 (s, 1H), 6.32 (s, 1H), 5.85 (s, 1H), 5.75 (m, 1H), 5.22 (s, 1H), 5.16−5.01 (m, 2H), 4.13 (broad s, 1H), 3.16 (broad s, 1H), 2.39 (s, 2H). LCMS (m/z): 260 (M + H+). N-(But-3-en-1-yl)-2,2,2-trifluoro-N-(1-(thiophen-2-yl)vinyl)acetamide (12). Yellow oil. 19.9 g, 72% yield. Eluent for chromatography: hexanes/EtOAc = 7/1. 1H NMR (500 MHz, chloroformd) δ 7.29 (dd, J = 5.0, 1.4 Hz, 1H), 7.14−6.81 (m, 2H), 5.91−5.57 (m, 2H), 5.28−4.92 (m, 3H), 4.14 (broad s, 1H), 3.13 (broad s, 1H), 2.40 (s, 2H). 13C NMR (126 MHz, chloroform-d) δ 157.2 (q, J = 35.9 Hz), 139.2, 138.2, 134.2, 127.9, 127.0, 126.1, 117.6, 116.5 (q, J = 288.2 Hz), 114.5, 47.6, 31.6. 19F NMR (376 MHz, chloroform-d) δ −67.68. LCMS (m/z): 276 (M + H+). Anal. Calcd for C12H12F3NOS: C, 52.36; H, 4.39; N, 5.09; S, 11.65. Found: C, 52.65; H, 4.08; N, 4.86; S, 11.33. N-(But-3-en-1-yl)-2,2,2-trifluoro-N-(1-(1-methyl-1H-pyrazol4-yl)vinyl)acetamide (13). Slightly yellow solid. 2.3 g, 83% yield. Eluent for chromatography: MTBE. 1H NMR (400 MHz, chloroform-d) δ 7.42 (s, 1H), 7.32 (s, 1H), 5.62 (m, 1H), 5.43 (s, 1H), 4.95 (m, 3H), 4.19−3.84 (broad s, 1H), 3.78 (s, 3H), 3.08 (broad s, 1H), 2.26 (m, 2H). 13C NMR (101 MHz, chloroform-d) δ 156.8 (q, J = 35.7 Hz), 137.3, 136.0, 134.1, 128.2, 118.6, 117.2, 116.4 (q, J = 288.1 Hz), 112.7 (q, J = 2.0 Hz), 46.8, 39.0, 31.3. 19F NMR (376 MHz, chloroform-d) δ −67.71. LCMS (m/z): 274 (M + H+). Anal. Calcd for C12H14F3N3O: C, 52.75; H, 5.16; N, 15.38. Found: C, 52.46; H, 5.38; N, 15.69. N-(1-(4-Bromophenyl)vinyl)-N-(but-3-en-1-yl)-2,2,2-trifluoroacetamide (14). Yellow oil. 2.7 g, 78% yield. Eluent for chromatography: hexanes/EtOAc = 10/1. 1H NMR (400 MHz, chloroform-d) δ 7.49 (d, J = 8.5 Hz, 2H), 7.25 (d, J = 8.5 Hz, 2H), 6.02−5.55 (m, 2H), 5.26 (s, 1H), 5.18−4.77 (m, 2H), 4.07 (broad s, 1H), 3.23−2.59 (broad s, 1H), 2.31 (q, J = 5.6 Hz, 2H). 19F NMR (376 MHz, chloroform-d) δ −67.32. LCMS (m/z): 348, 350 (M + H+). Anal. Calcd for C14H13BrF3NO: C, 48.30; H, 3.76; N, 4.02. Found: C, 48.62; H, 3.82; N, 3.83. N-(But-3-en-1-yl)-2,2,2-trifluoro-N-(1-(4-iodophenyl)vinyl)acetamide (15). Yellow oil. 2.7 g, 67% yield. Eluent for chromatography: hexanes/EtOAc = 10/1. 1H NMR (400 MHz, chloroform-d) δ 7.71 (d, J = 8.2 Hz, 2H), 7.12 (d, J = 8.2 Hz, 2H), 5.81 (s, 1H), 5.69 (m, 1H), 5.28 (s, 1H), 5.16−4.84 (m, 2H), 4.07 (broad s, 1H), 2.89 (broad s, 1H), 2.32 (m, 2H). 13C NMR (101 MHz, chloroform-d) δ 157.4 (q, J = 35.9 Hz), 142.5, 138.1, 134.0, 133.6, 127.8, 117.5, 116.4 (q, J = 288.2 Hz), 115.7, 95.6, 46.8, 31.2. 19F NMR (376 MHz, chloroform-d) δ −67.31. LCMS (m/z): 396 (M + H+). Anal. Calcd for C14H13F3INO: C, 42.55; H, 3.32; N, 3.54. Found: C, 42.63; H, 3.45; N, 3.71. 2,2,2-Trifluoro-1-(1-phenyl-2-azabicyclo[3.2.0]heptan-2-yl)ethan-1-one (7a). Enamide 7 (26.9 g, 100 mmol, 1.0 equiv) and benzophenone (1.82 g, 10.0 mmol, 0.1 equiv) were mixed in dry acetonitrile (1 L). The reaction mixture was degassed by bubbling of argon for 15 min and then irradiated at 365 nm. After 48 h of irradiation (the reaction was monitored by NMR), the solvent was evaporated under reduced pressure. The residue was purified via column chromatography (hexanes/EtOAc = 10/1) to get the product (23.4 g, 87% yield) as a yellow oil. 1H NMR (400 MHz, chloroform-d) δ 7.39−7.15 (m, 5H, Ph), 4.16 (m, 2H, 3-CH2), 3.07−2.76 (m, 2H, 5-CH, 7-CHH), 2.45 (ddd, J = 14.0, 9.3, 4.0 Hz, 1H, 7-CHH),

2.39−2.26 (m, 1H, 4-CHH), 2.26−2.10 (m, 1H, 6-CHH), 2.03 (dt, J = 14.0, 5.6 Hz, 1H, 4-CHH), 1.82 (dq, J = 12.1, 8.8 Hz, 1H, 6-CHH). 13 C NMR (126 MHz, chloroform-d) δ 154.6 (q, J = 36.6 Hz, COCF3), 141.7 (C, Ph), 128.5 (CH, Ph), 127.0 (CH, Ph), 125.3 (CH, Ph), 116.0 (q, J = 288.6 Hz, CF3), 72.7 (1-C), 48.1 (3-CH2), 46.4 (5-CH), 29.6 (CH2), 26.9 (CH2), 20.5 (6-CH2). 19F NMR (376 MHz, chloroform-d) δ −73.39. LCMS (m/z): 270 (M + H+). Anal. Calcd for C14H14F3NO: C, 62.45; H, 5.24; N, 5.20. Found: C, 62.70; H, 4.92; N, 5.23. 1-(1-(2,4-Dimethoxyphenyl)-2-azabicyclo[3.2.0]heptan-2yl)-2,2,2-trifluoroethan-1-one (8a). Yellow oil. 1.5 g, 78% yield. Eluent for chromatography: hexanes/MTBE = 40/1, then hexanes/ MTBE = 4/1. 1H NMR (400 MHz, chloroform-d) δ 7.38 (d, J = 8.4 Hz, 1H), 6.47 (dd, J = 8.4, 2.4 Hz, 1H), 6.39 (d, J = 2.4 Hz, 1H), 4.09 (t, J = 7.5 Hz, 2H), 3.77 (s, 3H), 3.73 (s, 3H), 3.06 (q, J = 7.8 Hz, 1H), 2.89 (dt, J = 12.7, 9.4 Hz, 1H), 2.62−2.37 (m, 2H), 2.23−2.06 (m, 1H), 1.98−1.85 (m, 1H), 1.72 (ddd, J = 16.3, 12.7, 8.0 Hz, 1H). 13 C NMR (101 MHz, chloroform-d) δ 160.2, 157.6, 154.2 (q, J = 36.1 Hz), 131.0, 121.3, 116.2 (q, J = 288.8 Hz), 103.4, 98.6, 71.4, 55.2, 54.9, 48.7 (q, J = 3.8 Hz), 44.8, 31.4, 26.9, 21.6. 19F NMR (376 MHz, chloroform-d) δ −73.37. LCMS (m/z): 330 (M + H+). Anal. Calcd for C16H18F3NO3: C, 58.35; H, 5.51; N, 4.25. Found: C, 58.67; H, 5.56; N, 4.43. 2,2,2-Trifluoro-1-(1-(pyridin-3-yl)-2-azabicyclo[3.2.0]heptan2-yl)ethan-1-one (9a). Yellow oil. 15.2 g, 83% yield. Eluent for chromatography: hexanes/MTBE = 1/1, then MTBE. 1H NMR (500 MHz, chloroform-d) δ 8.56−8.44 (s, 1H), 8.41 (d, J = 4.8 Hz, 1H), 7.55 (d, J = 8.0 Hz, 1H), 7.18 (dd, J = 8.0, 4.8 Hz, 1H), 4.11 (m, 2H), 2.95 (q, J = 7.7 Hz, 1H), 2.82 (dt, J = 13.1, 9.5 Hz, 1H), 2.38 (ddd, J = 13.1, 9.5, 3.9 Hz, 1H), 2.26 (m, 1H), 2.15 (m, 1H), 2.07− 1.90 (m, 1H), 1.81 (m, 1H). 13C NMR (126 MHz, chloroform-d) δ 155.0 (q, J = 36.9 Hz), 148.4, 147.3, 137.3, 133.6, 123.1, 116.1 (q, J = 288.3 Hz), 71.1, 48.2 (q, J = 3.8 Hz), 46.4, 29.8, 26.9, 20.6. 19F NMR (376 MHz, chloroform-d) δ −73.51. LCMS (m/z): 271 (M + H+). Anal. Calcd for C13H13F3N2O: C, 57.78; H, 4.85; N, 10.37. Found: C, 57.95; H, 4.67; N, 10.55. 2,2,2-Trifluoro-1-(1-(pyrazin-2-yl)-2-azabicyclo[3.2.0]heptan-2-yl)ethan-1-one (10a). Yellow oil. 1.1 g, 91% yield. Eluent for chromatography: MTBE. 1H NMR (500 MHz, chloroform-d) δ 8.49 (d, J = 1.5 Hz, 1H), 8.41 (dd, J = 2.6, 1.5 Hz, 1H), 8.32 (d, J = 2.6 Hz, 1H), 4.10 (m, 2H), 3.06 (dt, J = 12.9, 9.6 Hz, 1H), 2.96 (q, J = 7.8 Hz, 1H), 2.26 (m, 2H), 2.19−2.02 (m, 1H), 2.02−1.86 (m, 1H), 1.86−1.69 (m, 1H). 13C NMR (126 MHz, chloroform-d) δ 155.5, 155.1 (q, J = 37.1 Hz), 143.8, 142.9, 142.3, 116.1 (q, J = 288.0 Hz), 72.2, 48.6 (q, J = 3.6 Hz), 45.4, 29.7, 26.1, 20.4. 19F NMR (376 MHz, chloroform-d) δ −73.55. LCMS (m/z): 272 (M + H+). Anal. Calcd for C12H12F3N3O: C, 53.14; H, 4.46; N, 15.49. Found: C, 53.39; H, 4.71; N, 15.40. 2,2,2-Trifluoro-1-(1-(furan-2-yl)-2-azabicyclo[3.2.0]heptan-2yl)ethan-1-one (11a). Yellow oil. 10.5 g, 51% yield. Eluent for chromatography: hexanes/EtOAc = 10/1. 1H NMR (400 MHz, chloroform-d) δ 7.28 (s, 1H), 6.29 (d, J = 3.4 Hz, 1H), 6.17 (d, J = 3.4 Hz, 1H), 4.05 (m, 2H), 3.04 (q, J = 7.5 Hz, 1H), 2.78 (m, 1H), 2.40 (ddd, J = 13.3, 9.3, 4.3 Hz, 1H), 2.33−2.03 (m, 2H), 1.95 (m, 1H), 1.77 (m, 1H). 13C NMR (126 MHz, chloroform-d) δ 154.9 (q, J = 36.2 Hz), 153.8, 141.5, 116.1 (q, J = 289.6 Hz), 110.4, 106.0, 67.7, 48.2, 44.2, 29.7, 27.3, 20.6. 19F NMR (376 MHz, chloroform-d) δ −73.34. LCMS (m/z): 260 (M + H+). Anal. Calcd for C12H12F3NO2: C, 55.60; H, 4.67; N, 5.40. Found: C, 55.82; H, 4.54; N, 5.23. 2,2,2-Trifluoro-1-(1-(thiophen-2-yl)-2-azabicyclo[3.2.0]heptan-2-yl)ethan-1-one (12a). Yellow oil. 12.1 g, 93% yield. Eluent for chromatography: hexanes/EtOAc = 5/1. 1H NMR (400 MHz, chloroform-d) δ 7.17 (dd, J = 3.8, 2.6 Hz, 1H), 6.94 (m, 2H), 4.25−3.93 (m, 2H), 3.01 (q, J = 7.8 Hz, 1H), 2.82 (dt, J = 12.8, 9.4 Hz, 1H), 2.56 (m, 1H), 2.42−2.07 (m, 2H), 1.98 (m, 1H), 1.80 (m, 1H). 13 C NMR (126 MHz, chloroform-d) δ 154.9 (q, J = 37.0 Hz), 146.5, 126.9, 124.2, 123.8, 116.2 (q, J = 288.2 Hz), 70.2, 48.2 (q, J = 3.8 Hz), 47.4, 29.4, 29.2, 20.4. 19F NMR (376 MHz, chloroform-d) δ −73.50. LCMS (m/z): 276 (M + H+). Anal. Calcd for C12H12F3NOS: C, 1398

DOI: 10.1021/acs.joc.7b02910 J. Org. Chem. 2018, 83, 1394−1401

Article

The Journal of Organic Chemistry

19.7 (s). LCMS (m/z): 175 (M + H+). Anal. Calcd for C11H14N2: C, 75.82; H, 8.10; N, 16.08. Found: C, 75.66; H, 8.45; N, 16.23. 1-(Pyrazin-2-yl)-2-azabicyclo[3.2.0]heptane Hydrochloride (10b·HCl). White solid. 420 mg, 85% yield. 1H NMR (400 MHz, deuterium oxide) δ 8.80 (d, J = 1.6 Hz, 1H), 8.49 (dd, J = 2.7, 1.6 Hz, 1H), 8.43 (d, J = 2.7 Hz, 1H), 3.90−3.48 (m, 2H), 3.25 (s, 1H), 2.70− 2.50 (m, 1H), 2.50−2.20 (m, 2H), 2.11−1.87 (m, 2H), 1.78−1.60 (m, 1H). 13C NMR (101 MHz, deuterium oxide) δ 153.7, 144.6, 142.4, 140.6, 70.2, 45.7, 42.9, 30.3, 27.5, 19.1. LCMS (m/z): 176 (M − Cl−). Anal. Calcd for C10H14ClN3: C, 56.74; H, 6.67; N, 19.85. Found: C, 56.60; H, 6.84; N, 19.62. 1-(Furan-2-yl)-2-azabicyclo[3.2.0]heptane (11b). Colorless oil. 9.1 g, 90% yield. 1H NMR (400 MHz, chloroform-d) δ 7.29 (s, 1H), 6.25 (s, 1H), 6.13 (s, 1H), 3.35−3.20 (m, 2H), 2.88 (m, 1H), 2.56 (m, 1H), 2.12−1.46 (m, 5H), 1.36 (m, 1H). 13C NMR (101 MHz, chloroform-d) δ 158.8, 141.4, 110.0, 104.1, 64.7, 46.7, 44.1, 33.3, 31.3, 19.6. LCMS (m/z): 164 (M + H+). Anal. Calcd for C10H13NO: C, 73.59; H, 8.03; N, 8.58. Found: C, 73.85; H, 8.41; N, 8.21. 1-(Thiophen-2-yl)-2-azabicyclo[3.2.0]heptane Hydrochloride (12b·HCl). Mp 178−179 °C. White solid. 10.3 g, 97% yield. 1 H NMR (400 MHz, deuterium oxide) δ 7.41 (d, J = 5.2 Hz, 1H), 7.11 (d, J = 2.8 Hz, 1H), 7.00 (dd, J = 5.2, 2.8 Hz, 1H), 3.76−3.60 (m, 2H), 3.33 (m, 1H), 2.53 (m, 2H), 2.21 (m, 2H), 2.04−1.93 (m, 1H), 1.65 (m, 1H). 13C NMR (101 MHz, deuterium oxide) δ 141.3, 127.8, 127.4, 126.6, 67.6, 46.0, 43.4, 30.6, 29.5, 19.1. LCMS (m/z): 180 (M − Cl−). Anal. Calcd for C10H14ClNS: C, 55.67; H, 6.54; N, 6.49; S, 14.86. Found: C, 55.78; H, 6.32; N, 6.81; S, 14.59. Crystals of 12b· HCl, suitable for an X-ray diffraction study, were obtained by a slow evaporation of a diluted solution of 12b·HCl in methanol. 1-(1-Methyl-1H-pyrazol-4-yl)-2-azabicyclo[3.2.0]heptane Hydrochloride (13b·HCl). White solid. 610 mg, 93% yield. 1H NMR (400 MHz, deuterium oxide) δ 7.90 (s, 1H), 7.80 (s, 1H), 3.87 (s, 3H), 3.77−3.55 (m, 2H), 3.19 (m, 1H), 2.45 (m, 2H), 2.34−2.09 (m, 2H), 1.98 (dd, J = 13.8, 5.8 Hz, 1H), 1.70−1.57 (m, 1H). 13C NMR (101 MHz, deuterium oxide) δ 135.4, 132.1, 120.8, 64.0, 45.9, 42.6, 38.3, 30.5, 28.6, 19.3. LCMS (m/z): 178 (M − Cl−). Anal. Calcd for C10H16ClN3: C, 56.20; H, 7.55; N, 19.66. Found: C, 56.55; H, 7.48; N, 19.28. 1-(Piperidin-3-yl)-2-azabicyclo[3.2.0]heptane (17). A solution of amine 9b (20.0 g, 115 mmol, 1.0 equiv) in MTBE (250 mL) was mixed with 10% aqueous solution of NaOH (25 g, 625 mmol, 5.4 equiv). The vigorously stirred reaction mixture was treated dropwise with Boc2O (30.0 g, 137 mmol, 1.2 equiv). After being stirred overnight, the organic layer was washed with 10% Na2SO4 solution (100 mL), dried over anhydrous Na2SO4, and evaporated. Hexanes (100 mL) were added to the residue, and the formed crystals were filtered and washed with hexanes (2 × 50 mL) to afford Boc-protected amine. The obtained product was dissolved in methanol (200 mL), treated with 10% palladium on charcoal (1.5 g, 14 mmol, 0.12 equiv), and stirred for 48 h at 50 °C under hydrogen atmosphere (60 atm.). Palladium on charcoal was filtered off, and the solution was evaporated to afford the product (26.1 g, 81% yield) as a colorless oil. 1H NMR of both diastereomers (400 MHz, chloroform-d) δ 3.69 (s, 1H), 3.44 (m, 1H), 3.17−2.71 (m, 3H), 2.43−1.97 (m, 4H), 1.95−1.66 (m, 4H), 1.66−1.41 (m, 6H), 1.36 (s, 9H). 13C NMR of both diastereomers (126 MHz, chloroform-d) δ 154.5 (s), 153.7 (s), 79.0 (s), 70.8 (s), 70.0 (s), 50.0 (s), 48.4 (s), 48.0 (s), 47.0 (s), 41.5 (s), 40.1 (s), 39.1 (s), 29.1 (s), 28.6 (s), 27.8 (s), 27.2 (s), 25.9 (s), 20.6 (s), 20.4 (s). LCMS (m/z): 281 (M + H+). Anal. Calcd for C16H28N2O2: C, 68.53; H, 10.06; N, 9.99. Found: C, 68.90; H, 9.95; N, 10.11. 2-Azabicyclo[3.2.0]heptane-1-carboxylic Acid Hydrochloride (18). A solution of 11b (5.0 g, 30.7 mmol, 1.0 equiv) and pyridine (3.2 g, 40.5 mmol, 1.3 equiv) in acetonitrile (30 mL) was cooled to −20 °C under inert atmosphere. Benzoyl chloride (5.2 g, 37.0 mmol, 1.2 equiv) was added dropwise, and the reaction mixture was stirred overnight and evaporated under reduced pressure. The residue was dissolved in MTBE (100 mL), and the formed solution was washed with 10% aqueous citric acid (100 mL) and saturated aqueous NaHCO3 (100 mL), dried over Na2SO4, and evaporated to yield protected amide.

52.36; H, 4.39; N, 5.09; S, 11.65. Found: C, 52.03; H, 4.67; N, 5.00; S, 11.45. 2,2,2-Trifluoro-1-(1-(1-methyl-1H-pyrazol-4-yl)-2-azabicyclo[3.2.0]heptan-2-yl)ethan-1-one (13a). Yellow oil. 1.2 g, 91% yield. Eluent for chromatography: MTBE, then EtOAc. 1H NMR (400 MHz, chloroform-d) δ 7.31 (s, 2H), 4.02 (q, J = 7.8 Hz, 2H), 3.84 (s, 3H), 3.14−2.92 (m, 1H), 2.63−2.40 (m, 2H), 2.40−2.09 (m, 2H), 2.09− 1.88 (m, 1H), 1.77 (m, 1H). 13C NMR (126 MHz, chloroform-d) δ 154.9 (q, J = 36.3 Hz), 136.5, 128.5, 123.9, 116.3 (q, J = 288.5 Hz), 66.9, 48.0 (q, J = 3.8 Hz), 45.7, 39.0, 29.8, 29.7, 20.8. 19F NMR (376 MHz, chloroform-d) δ −73.43. LCMS (m/z): 274 (M + H+). Anal. Calcd for C12H14F3N3O: C, 52.75; H, 5.16; N, 15.38. Found: C, 52.97; H, 5.05; N, 15.29. 1-(1-(4-Bromophenyl)-2-azabicyclo[3.2.0]heptan-2-yl)-2,2,2trifluoroethan-1-one (14a). Enamide 14 (0.35 g, 1.0 mmol, 1.0 equiv) was mixed in dry acetonitrile (40 mL). The reaction mixture was degassed by bubbling argon for 15 min, and Ir(ppy)3 (0.13 g, 0.2 mmol, 0.2 equiv) was added. The reaction mixture was irradiated at 419 nm for 2 weeks and evaporated under reduced pressure. The residue was purified via reverse-phase column chromatography (gradient H2O/acetonitrile from 50/50 to 25/75) to get the product (0.12 g, 34% yield) as a yellow oil. 1H NMR (500 MHz, chloroform-d) δ 7.45 (d, J = 8.2 Hz, 2H), 7.15 (d, J = 8.2 Hz, 2H), 4.16 (m, 2H), 2.95 (q, J = 7.7 Hz, 1H), 2.86 (m, 1H), 2.44 (m, 1H), 2.32 (m, 1H), 2.18 (m, 1H), 2.04 (m, 1H), 1.83 (m, 1H). 13C NMR (126 MHz, chloroform-d) δ 154.9 (q, J = 36.9 Hz), 140.9, 131.4, 127.3, 121.1, 116.1 (q, J = 288.3 Hz), 72.3, 48.1 (q, J = 4.0 Hz), 46.4, 29.7, 27.0, 20.4. 19F NMR (376 MHz, chloroform-d) δ −73.48. LCMS (m/z): 348, 350 (M + H+). Anal. Calcd for C14H13BrF3NO: C, 48.30; H, 3.76; N, 4.02. Found: C, 48.14; H, 3.56; N, 3.99. 1-Phenyl-2-azabicyclo[3.2.0]heptane (7b). Amide 7a (25.0 g, 93 mmol, 1.0 equiv) and NaOH (7.4 g, 186 mmol, 2.0 equiv) were dissolved in methanol (250 mL). The reaction mixture stirred overnight and evaporated. Methyl tert-butyl ether (250 mL) and water (150 mL) were added to the residue. The organic layer was separated, washed with water (150 mL), and acidified with 2 N aqueous hydrochloric acid (150 mL). Aqueous layer was separated and washed with methyl tert-butyl ether (150 mL). Then 2 N aqueous NaOH (200 mL) added to the aqueous solution, and it was extracted with MTBE (3 × 200 mL). The combined organic layers were dried over anhydrous Na2SO4 and evaporated to give product (12.6 g, 78% yield) as a colorless oil. 1 H NMR (400 MHz, chloroform-d) δ 7.48−7.10 (m, 5H), 3.45−3.20 (m, 2H), 3.06 (q, J = 7.4 Hz, 1H), 2.54 (m, 1H), 2.32−2.00 (m, 2H), 1.93−1.64 (m, 3H), 1.46 (m, 1H). 13C NMR (126 MHz, chloroform-d) δ 147.0, 128.4, 126.6, 125.4, 69.7, 47.3, 44.7, 34.5, 33.62, 19.8. LCMS (m/z): 174 (M + H+). Anal. Calcd for C12H15N: C, 83.19; H, 8.73; N, 8.08. Found: C, 83.01; H, 8.80; N, 8.31. Crystals of 7b·HCl, suitable for an X-ray diffraction study, were obtained by a slow evaporation of a diluted solution of 7b·HCl in methanol. 1-(2,4-Dimethoxyphenyl)-2-azabicyclo[3.2.0]heptane Hydrocloride (8b·HCl). White solid. 550 mg, 89% yield. 1H NMR (500 MHz, deuterium oxide) of both rotamers δ 7.29 (s, 1H, CH, Ar), 6.69−6.48 (m, 2H, 2 × CH, Ar), 3.78 (s, 6H, 2 × CH3), 3.65 (m, 2H, CH2NH2), 3.43 (s, 1H, CH), 2.53−2.39 (m, 2H, CCH2), 2.15 (m, 2H, CHHCHCHH), 2.00 (m, 1H, CHHCH2N), 1.66 (d, J = 8.1 Hz, 1H, CCH2CHHCH). 13C NMR (101 MHz, deuterium oxide) of both rotamers δ 161.2, 161.1 (2 × s, C, Ar), 158.1 (s, C, Ar), 127.9, 127.8 (2 × s, CH, Ar), 118.0 (s, C, Ar), 104.7 (s, CH, Ar), 98.9 (s, CH, Ar), 69.8 (s, C), 55.5 (s, CH3), 55.2 (s, CH3), 45.5 (s, CH2N), 40.1 (s, CH), 30.4 (s, CH2CH2N), 28.0 (s, CCH2), 19.1 (s, CCH2CH2CH). LCMS (m/z): 234 (M − Cl−). Anal. Calcd for C14H20ClNO2: C, 62.33; H, 7.47; N, 5.19. Found: C, 62.48; H, 7.64; N, 5.46. 1-(Pyridin-3-yl)-2-azabicyclo[3.2.0]heptane (9b). Colorless oil. 8.5 g, 91% yield. 1H NMR (400 MHz, chloroform-d) δ 8.54 (s), 8.38 (d, J = 4.6 Hz, 1H), 7.56 (d, J = 7.6 Hz, 1H), 7.14 (dd, J = 7.6, 4.6 Hz, 1H), 3.42−3.14 (m, 2H), 3.07−2.80 (m, 1H), 2.50−2.34 (m, 1H), 2.25−1.90 (m, 3H), 1.84−1.49 (m, 2H), 1.49−1.20 (m, 1H). 13 C NMR (126 MHz, chloroform-d) δ 147.7 (s), 147.3 (s), 142.0 (s), 132.9 (s), 123.0 (s), 67.4 (s), 46.8 (s), 44.6 (s), 33.7 (s), 33.2 (s), 1399

DOI: 10.1021/acs.joc.7b02910 J. Org. Chem. 2018, 83, 1394−1401

The Journal of Organic Chemistry

■

The crude product was dissolved in acetonitrile (50 mL) and added under inert atmosphere to a vigorously stirred mixture of NaIO4 (40.0 g, 187 mmol, 6.1 equiv), RuCl3·H2O (0.35 g, 1.5 mmol, 0.05 equiv), H2O (200 mL), CCl4 (300 mL), and acetonitrile (200 mL). The reaction mixture was stirred for 1 h. The color of the solution turned from yellowish to black. Then enough NaIO4 was added to restore the yellowish color. The reaction mixture was stirred for 1 h and then diluted with water (500 mL) and extracted with EtOAc (3 × 500 mL). The combined organic layers were washed with 20% aqueous NaHSO3 until colorless and brine and dried over magnesium sulfate, and the solvent was evaporated under reduced pressure. This residue was dissolved in saturated aqueous K2CO3 (500 mL) and washed with EtOAc (2 × 500 mL). The aqueous layer was acidified to pH 2 by addition of 2 N HCl and extracted with CH2Cl2 (2 × 500 mL). The combined organic layers were dried over Na2SO4 and evaporated to give N-protected amino acid. Concentrated HCl (100 mL) was added to the product and heated at reflux for 24 h. The reaction mixture was evaporated, diluted with water (200 mL), washed with EtOAc (3 × 100 mL), and evaporated to afford the product (2.5 g, 47% yield) as a slightly yellow solid. 1 H NMR (400 MHz, DMSO-d6) δ 10.68 (broad s, 1H), 8.95 (broad s, 1H), 3.52 (m, 2H), 3.13 (m, 1H), 2.59−2.30 (m, 3H), 2.19 (m, 1H), 1.93 (m, 1H), 1.82 (dd, J = 12.5, 4.6 Hz, 1H), 1.70 (m, 1H). 13C NMR (101 MHz, DMSO-d6) δ 171.3 (s), 68.1 (s), 45.7 (s), 40.9 (s), 30.3 (s), 24.5 (s), 20.3 (s). LCMS (m/z): 142 (M − Cl−). Anal. Calcd for C7H12ClNO2: C, 47.33; H, 6.81; N, 7.89. Found: C, 47.65; H, 6.48; N, 8.02. 2,2,2-Trifluoro-1-(1-(5-iodo-2,4-dimethoxyphenyl)-2azabicyclo[3.2.0]heptan-2-yl)ethan-1-one (19). To a stirred solution of EtOAc (20 mL), acetonitrile (20 mL) and water (40 mL) were added NaIO4 (4.0 g, 18.8 mmol, 4.1 equiv), 8b (1.5 g, 4.6 mmol, 1.0 equiv), and RuCl3 (0.04 g, 0.19 mmol, 0.047 equiv). The reaction mixture was stirred overnight under inert atmosphere at room temperature. EtOAc (200 mL) and water (200 mL) were added. The organic layer was separated, and the aqueous layer was washed with EtOAc (200 mL). The combined organic layers were dried over Na2SO4 and evaporated. The brown residue was purified by column chromatography to afford the product as white crystals (1.6 g, 76% yield). 1 H NMR (400 MHz, chloroform-d) δ 7.75 (s, 1H), 6.33 (s, 1H), 4.08 (t, J = 7.4 Hz, 2H), 3.83 (s, 3H), 3.77 (s, 3H), 3.01 (q, J = 7.9 Hz, 1H), 2.84 (q, J = 10.5 Hz, 1H), 2.48 (m, 1H), 2.42−2.28 (m, 1H), 2.14 (m, 1H), 1.93 (m, 1H), 1.77−1.59 (m, 1H). 13C NMR (101 MHz, chloroform-d) δ 158.4, 158.1, 154.2 (q, J = 36.0 Hz), 140.1, 123.4, 116.2 (q, J = 288.7 Hz), 95.6, 73.7, 70.9, 56.4, 55.2, 48.7 (q, J = 3.9 Hz), 45.0, 31.3, 26.9, 21.4.19F NMR (376 MHz, chloroform-d) δ −73.39. LCMS (m/z): 456 (M + H+). Anal. Calcd for C16H17F3INO3: C, 42.22; H, 3.76; N, 3.08. Found: C, 42.49; H, 3.59; N, 3.41. 2-Butyl-N-(2,6-dimethylphenyl)-2-azabicyclo[3.2.0]heptane1-carboxamide (24). The synthesis was performed according to the described procedure.4c White solid. 210 mg, 21% yield. 1H NMR (400 MHz, chloroform-d) δ 8.78 (s, 1H), 7.07 (s, 3H), 3.49−3.32 (m, 1H), 2.99 (dd, J = 14.0, 7.4 Hz, 1H), 2.87−2.65 (m, 2H), 2.61− 2.46 (m, 2H), 2.25−2.12 (m, 6H), 2.04−1.88 (m, 2H), 1.66 (dd, J = 12.5, 5.3 Hz, 2H), 1.57−1.20 (m, 4H), 0.93 (t, J = 7.3 Hz, 3H). 13C NMR (101 MHz, chloroform-d) δ 172.7 (s), 135.1 (s), 134.4 (s), 128.1 (s), 126.7 (s), 72.0 (s), 51.5 (s), 49.7 (s), 44.8 (s), 31.8 (s), 30.4 (s), 20.8 (s), 20.3 (s), 18.4 (s), 16.0 (s), 14.1 (s). LCMS (m/z): 301 (M + H+). Anal. Calcd for C19H28N2O: C, 75.96; H, 9.39; N, 9.32. Found: C, 76.16; H, 9.05; N, 9.48.

■

Article

AUTHOR INFORMATION

Corresponding Author

*E-mail: [email protected]; www.mykhailiukchem. org. ORCID

Pavel K. Mykhailiuk: 0000-0003-1821-9011 Author Contributions

The manuscript was written through contributions of all authors. All authors gave approval to the final version of the manuscript. Notes

The authors declare no competing financial interest.

■

ACKNOWLEDGMENTS The authors are grateful to Prof. A. Tolmachev for financial support, to Dr. A. Kozitskiy for 2D NMR spectra, to Dr. S. Shishkina for X-ray analysis, to Prof. I. Komarov for fruitful discussions, and to I. Pervak for help with ozonolysis.

■

REFERENCES

(1) (a) Mann, A. Conformational restriction and/or steric hindrance in medicinal chemistry. In The Practice of Medicinal Chemistry, 3rd ed.; Wermuth, C. G., Ed.; Academic Press/Elsevier: Amsterdam, 2008; p 363. (b) Komarov, I. V.; Grigorenko, A. O.; Turov, A. V.; Khilya, V. P. Russ. Chem. Rev. 2004, 73, 785. (2) (a) Giannis, A.; Kolter, T. Angew. Chem., Int. Ed. Engl. 1993, 32, 1244. (b) Vagner, J.; Qu, H.; Hruby, V. J. Curr. Opin. Chem. Biol. 2008, 12, 292. (c) Ripka, A. S.; Rich, D. H. Curr. Opin. Chem. Biol. 1998, 2, 441. (3) (a) Wlochal, J.; Davies, R. D. M.; Burton, J. Org. Lett. 2014, 16, 4094. (b) Chalmers, B. A.; Xing, H.; Houston, S.; Clark, C.; Ghassabian, S.; Kuo, A.; Cao, B.; Reitsma, A.; Murray, C.-E. P.; Stok, J. E.; Boyle, G. M.; Pierce, C. J.; Littler, S. W.; Winkler, D. A.; Bernhardt, P. V.; Pasay, C.; De Voss, J. J.; McCarthy, J.; Parsons, P. G.; Walter, G. H.; Smith, M. T.; Cooper, H. M.; Nilsson, S. K.; Tsanaktsidis, J.; Savage, G. P.; Williams, C. M. Angew. Chem., Int. Ed. 2016, 55, 3580. (c) Burkhard, J. A.; Wagner, B.; Fischer, H.; Schuler, F.; Müller, K.; Carreira, E. M. Angew. Chem., Int. Ed. 2010, 49, 3524. (d) Stepan, A. F.; et al. J. Med. Chem. 2012, 55, 3414. (e) Meanwell, N. A. J. Med. Chem. 2011, 54, 2529. (4) Our contribution: (a) Druzhenko, T.; Denisenko, O.; Kheylik, Y.; Zozulya, S.; Shishkina, S.; Tolmachev, A.; Mykhailiuk, P. K. Org. Lett. 2015, 17, 1922. (b) Denisenko, A. V.; Mityuk, A. P.; Grygorenko, O. O.; Volochnyuk, D. M.; Shishkin, O. V.; Tolmachev, A. A.; Mykhailiuk, P. K. Org. Lett. 2010, 12, 4372. (c) Kirichok, A. A.; Shton, I.; Kliachyna, M.; Pishel, I.; Mykhailiuk, P. K. Angew. Chem., Int. Ed. 2017, 56, 8865. (d) Chalyk, B.; Isakov, A.; Butko, M.; Hrebeniuk, K.; Savych, O.; Kucher, O.; Gavrilenko, K.; Druzhenko, T.; Yarmolchuk, V.; Zozulya, S.; Mykhailiuk, P. K. Eur. J. Org. Chem. 2017, 31, 4530. (e) Chalyk, B.; Butko, M.; Yanshyna, O.; Gavrilenko, K.; Druzhenko, T.; Mykhailiuk, P. K. Chem. - Eur. J. 2017, 23, 16782. (5) The search was performed at www.drugbank.ca and www.ebi.ac. uk/chembl databases in July 2017. (6) More than 1000 papers on the topic: (a) Kriis, K.; Ausmees, K.; Pehk, T.; Lopp, M.; Kanger, T. Org. Lett. 2010, 12, 2230. (b) Pedrosa, R.; Andrés, C.; Nieto, J.; del Pozo, S. J. Org. Chem. 2003, 68, 4923. (c) Denisenko, A. V.; Druzhenko, T.; Skalenko, Y.; Samoilenko, M.; Grygorenko, O. O.; Zozulya, S.; Mykhailiuk, P. K. J. Org. Chem. 2017, 82, 9627. (d) Gonzalez, A.; Benitez, D.; Tkatchouk, E.; Goddard, W.; Toste, D. J. Am. Chem. Soc. 2011, 133, 5500. (e) Artamonov, O. S.; Slobodyanyuk, E. Y.; Volochnyuk, D. M.; Komarov, I. V.; Tolmachev, A. A.; Mykhailiuk, P. K. Eur. J. Org. Chem. 2014, 2014, 3592. (7) Tricyclic systems containing core D: (a) Basler, B.; Schuster, O.; Bach, T. J. Org. Chem. 2005, 70, 9798. (b) Albrecht, D.; Basler, B.; Bach, T. J. Org. Chem. 2008, 73, 2345. (c) Fort, D. A.; Woltering, T. J.; Nettekoven, M.; Knust, H.; Bach, T. Angew. Chem., Int. Ed. 2012, 51, 10169. (d) Ikeda, M.; Ohno, K.; Homma, K.; Ishibashi, H.; Tamura, Y.

ASSOCIATED CONTENT

* Supporting Information S

The Supporting Information is available free of charge on the ACS Publications website at DOI: 10.1021/acs.joc.7b02910. Copies of NMR spectra and X-ray crystallography data (PDF) CIF data for 7b (CIF) CIF data for 12b (CIF) CIF data for 18 (CIF) 1400

DOI: 10.1021/acs.joc.7b02910 J. Org. Chem. 2018, 83, 1394−1401

Article

The Journal of Organic Chemistry Chem. Pharm. Bull. 1981, 29, 2062. (e) Roupany, A. J. A.; Baker, J. R. RSC Adv. 2013, 3, 10650. (f) Blanco-Ania, D.; Gawade, S. A.; Zwinkels, L. J. L.; Maartense, L.; Bolster, M. G.; Benningshof, J. C. J.; Rutjes, F. P. J. T. Org. Process Res. Dev. 2016, 20, 409. (g) Tang, P. C.; Lin, Z. G.; Wang, Y.; Yang, F. L.; Wang, Q.; Fu, J. H.; Zhang, L.; Gong, A. S.; Luo, J. J.; Dai, J.; She, G. H.; Si, D. D.; Feng, J. Chin. Chem. Lett. 2010, 21, 253. (8) (a) Ciamician, G.; Silber, P. Ber. Dtsch. Chem. Ges. 1908, 41, 1928. (b) Poplata, S.; Troster, A.; Zou, Y.-Q.; Bach, T. Chem. Rev. 2016, 116, 9748. (9) Piotrowski, D. W. Synlett 1999, 1999 (7), 1091. (10) (a) Pirrung, M. C. Tetrahedron Lett. 1980, 21, 4577. (b) Hughes, P.; Martin, M.; Clardy, J. Tetrahedron Lett. 1980, 21, 4579. (c) Esslinger, C. S.; Koch, H. P.; Kavanaugh, M. P.; Philips, D. P.; Chamberlin, A. R.; Thompson, C. M.; Bridges, R. J. Bioorg. Med. Chem. Lett. 1998, 8, 3101. (d) Tkachenko, A. N.; Radchenko, D. S.; Mykhailiuk, P. K.; Grygorenko, O. O.; Komarov, I. V. Org. Lett. 2009, 11, 5674. (e) Malpass, J. R.; Patel, A. B.; Davies, J. W.; Fulford, S. Y. J. Org. Chem. 2003, 68, 9348. (f) Varnes, J. G.; Lehr, G. S.; Moore, G. L.; Hulsizer, J. M.; Albert, J. S. Tetrahedron Lett. 2010, 51, 3756. (g) Mykhailiuk, P. K.; Kubyshkin, V.; Bach, T.; Budisa, N. J. Org. Chem. 2017, 82, 8831. (11) Homoallylamine was previously used in the synthesis of polysubstituted 2-azabicyclo[3.2.0]heptanes: ref 7. (12) Pioneering work on the regioselectivity of substituted 1,6heptadienes: Matlin, A. R.; George, C. F.; Wolff, S.; Agosta, W. C. J. Am. Chem. Soc. 1986, 108, 3385. (13) We think that the reaction mechanism changes. Reaction at 366 nm/PhCOMe proceeds via the triplet biradical, while at 412 nm/ Ir(ppy)3 via the cation-radical. (14) (a) Ischay, M. A.; Lu, Z.; Yoon, T. P. J. Am. Chem. Soc. 2010, 132, 8572. (b) Prier, C. K.; Rankic, D. A.; MacMillan, D. W. C. Chem. Rev. 2013, 113, 5322. (15) CCDC numbers: 1521343 (7b), 1521342 (12b), 1521345 (18). (16) An alternative synthesis of 18 is described in a Ph.D. thesis available online: Kopylova, N.: 2010, Universität Konstanz: http://dnb.info/1006534660/34.

1401

DOI: 10.1021/acs.joc.7b02910 J. Org. Chem. 2018, 83, 1394−1401